Virulent Bacteriophages Can Target O104:H4 Enteroaggregative Escherichia coli in the Mouse Intestine

Abstract

cIn vivo bacteriophage targeting of enteroaggregative Escherichia coli (EAEC) was assessed using a mouse intestinal model of colonization with the O104:H4 55989Str strain and a cocktail of three virulent bacteriophages. The colonization model was shown to mimic asymptomatic intestinal carriage found in humans. The addition of the cocktail to drinking water for 24 h strongly decreased ileal and weakly decreased fecal 55989Str concentrations in a dose-dependent manner. These decreases in ileal and fecal bacterial concentrations were only transient, since 55989Str concentrations returned to their original levels 3 days later. These transient decreases were independent of the mouse microbiota, as similar results were obtained with axenic mice. We studied the infectivity of each bacteriophage in the ileal and fecal environments and found that 55989Str bacteria in the mouse ileum were permissive to all three bacteriophages, whereas those in the feces were permissive to only one bacteriophage. Our results provide the first demonstration that bacterial permissivity to infection with virulent bacteriophages is not uniform throughout the gut; this highlights the need for a detailed characterization of the interactions between bacteria and bacteriophages in vivo for the further development of phage therapy targeting intestinal pathogens found in the gut of asymptomatic human carriers. Bacteriophages-viruses that infect only bacteria -have been used for decades to treat human bacterial infections, mainly in Eastern Europe (2,19,24). The worldwide spread of panresistant bacteria and the shortage of new antibiotics are now leading to a worldwide revival of interest in phage therapy (43). Many studies of animal models have shown this therapeutic approach to be promising (8,14,28,40). However, markedly different results have been obtained depending on the animal model, the nature of the bacteriophages, and the application method used (36). Nevertheless, the narrow host spectrum of bacteriophages, which are often restricted to a particular bacterial subspecies, may make it possible to target pathogens without affecting commensal strains from the same bacterial species. Several studies have reported the use of bacteriophages to target enterotoxigenic, enteropathogenic, and commensal Escherichia coli strains (7). They reported a decrease in diarrheal symptoms (21,40,41), a decrease in the concentration of the bacterium in the intestine (10,(33)(34)(35), an increase in the rate of natural bacterial clearance (9, 39, 42), or even no decrease in the bacterial concentration at all (16,47). These data indicate that, within the scope of the intestinal microbiota, detailed investigations are required of the interactions between individual bacteriophages and their bacterial hosts, even within a single given bacterial species.Enteroaggregative E. coli (EAEC) is now recognized as an emerging intestinal pathogen (30). It is frequently found in the gut of asymptomatic human carriers, who serve as reservoirs for interhuman EAEC transmission (3...

Virulence of the Shiga Toxin Type 2-Expressing Escherichia coli O104:H4 German Outbreak Isolate in Two Animal Models

“…We further identified the main site of C227-11 colonization to be the cecum in both Amp-treated and ICF models, a finding that is in agreement with the findings obtained with other O104:H4 infection models (47,49,68). However, unlike Torres et al (47), we found that the O104:H4 outbreak strain clearly also colonized the small and large intestines.…”

“…However, unlike Torres et al (47), we found that the O104:H4 outbreak strain clearly also colonized the small and large intestines. That EAEC colonizes both the small and large intestines in an animal model was also shown by Harrington et al (44) and Maura et al (68). A correlation between the small intestinal colonization and virulence was demonstrated by Wadolkowski et al (66) in the Str-treated mouse model of STEC pathogenesis.…”

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…Cocktails of phages are therefore a promising strategy for fighting biofilms. Recently, a cocktail of three phages was shown to reduce mouse ileum colonization by an O104:H4 enteroaggregative strain of E. coli (364). The onset of potential resistance and long-term innocuity must now be evaluated in order to validate these strategies.…”

Aerosol Phage Therapy Efficacy in Burkholderia cepacia Complex Respiratory Infections

“…Phages can lyse a bacterial cell with acute specificity (often infecting only a few strains of a species), allowing for targeted treatment of a bacterial infection without disruption of the natural host microflora (17)(18)(19)(20)(21)(22)(23)(24)(25). Previous research using animal models has shown that phage therapy can be effective against a wide range of infections, including those involving burn (17,18), systemic (19), gut (20,21), and respiratory infections (22)(23)(24)(25).…”